The invention relates to the allylic oxidation of organic compounds.
Allylic oxidation is a fundamental organic reaction of significant interest to organic chemists practicing in a variety of fields from agricultural products to pharmaceuticals. A variety of procedures are known for oxidizing various organic compounds that possess allylically activated hydrogen(s), but such procedures typically suffer from unsatisfactory yields, tedious workups and/or require the use of expensive reagents.
Allylic oxidation reactions have traditionally been performed with chromium reagents, such as chromium trioxide and sodium/potassium dichromate. While generally effective, such reactions usually require a large excess of the reagent under harsh conditions (e.g., a large volume of aqueous acetic acid, anhydrous acetic acid (Fieser""s Reagent) or concentrated or dilute sulfuric acid). Chromium trioxide pyridine complex allows the oxidation to be carried out at ambient temperature, but requires the use of a large excess of the reagent (xcx9c20 equiv.) and is highly hygroscopic, making the reagent unattractive for large scale production.
Pyridinium chlorochromate (PCC) and pyridinium dichromate have more or less become ubiquitous for chromate based oxidations as they are generally effective and can be prepared by a procedure significantly less hazardous than that required to prepare the chromium trioxide-pyridine complex. However, these reagents also tend to require a large excess (xcx9c20 equiv.) of the reagent. The use of tert-butyl hydroperoxide in combination with a chromium reagent affords allylic oxidation under relatively mild processing conditions, but often requires the use of an undesirable organic solvent such as benzene.
A further drawback associated with the aforementioned procedures is the incomplete nature of the conversion, requiring the implementation of expensive techniques, such as chromatography, to remove unreacted starting material and obtain a product of sufficient purity.
Hence, a continuing need exists for a simple, efficient, safe and cost effective procedure for selectively effecting the allylic oxidation of organic compounds, particularly xcex945-steroids, suitable for use on a commercial scale.
We have discovered a simple, efficient, safe, and cost effective procedure for oxidizing organic compounds having allylic hydrogen atom(s). The procedure involves reactively contacting an organic compound having an allylic hydrogen atom(s) with a combination of a chromium compound and an N-hydroxy dicarboxylic acid imide under conditions sufficient to effect oxidation of the allylic hydrogen(s) on the organic compound.
The successful incorporation of an N-hydroxy imide of a suitable dicarboxylic acid with a chromium oxidant allows the reaction to be conveniently conducted at ambient or near ambient temperature and normal pressure using conventional, relatively safe organic solvents.
Definitions
As utilized herein, including the claims, the term xe2x80x9callylic compoundxe2x80x9d references an organic compound having at least one allylic hydrogen atom.
As utilized herein, including the claims, the term xe2x80x9callylic oxidation xe2x80x9d means oxidation of an allylic compound by replacing at least one allylic hydrogen(s) with oxygen or an oxygen-containing group.
As utilized herein, including the claims, the term xe2x80x9creactantsxe2x80x9d collectively references allylic substrates, N-hydroxy dicarboxylic acid imides and chromium-containing compounds. Solvents, including both aqueous and organic solvents, are specifically excluded from the definition of reactants.
Process
The present process is extremely useful both in terms of yield and operational simplicity. This is particularly true for the allylic substrates of xcex945-steroids and benzylic compounds. Excellent yields are obtained with low molar ratios of the reactants under ambient or near ambient conditions. Of particular interest is the discovery that the process achieves the desired allylic oxidation with a near total absence of any competitive side reactions.
The process involves reactively contacting an allylic compound with a combination of N-hydroxy dicarboxylic acid imide and a chromium-containing oxidant(s), under conditions sufficient to effect oxidation of the allylic hydrogen atom(s) on the organic compound. For example, an allylic compound can be dissolved in a suitable organic solvent and a mixture of the N-hydroxy dicarboxylic acid imide and chromium-containing oxidant(s) added. Water may optionally be incorporated into the reaction mixture in a suitable amount.
Constituents
Allylic Compounds
Allylic compounds are any organic compound incorporating the structure xe2x80x94RC1xe2x95x90C2Hxe2x80x94C3Hnxe2x80x94 within the molecule, wherein n is 1, 2 or 3. Hydrogen atoms attached to the C1 and C2 carbon atoms are referenced as vinylic hydrogen. Hydrogen atoms attached to the C3 carbon atom are referenced as allylic hydrogen. The process of this invention selectively oxidizes allylic hydrogen atoms over vinylic hydrogen atoms. Exemplary allylic compounds include specifically, but not exclusively, (i) aliphatic vinylic compound such as methyl oleate, (ii) aromatic benzylic compounds such as fluorene and diphenyl methane, (iii) isoprenoids, such as carotenoids, terpenes, sesquiterpenes and vitamins, and (iv) steroids and sterols, such as androstenes, cholesterol, estraenes, pregnenes and derivatives thereof such as esters, esters, and ketals of these compounds.
Of particular commercial interest is the allylic oxidation of steroids, particularly xcex945 steroids such as dehydroepiandrosterone and derivatives of dehydroepiandrosterone, because such steroids possess pharmacological activity and can be conveniently and effectively allylically oxidized in excellent yields by the process of this invention.
Cooxidants
The procedure utilizes a cooxidant system of N-hydroxy dicarboxylic acid imide and a chromium-containing oxidant.
A cooxidant system of a N-hydroxy dicarboxylic acid imide and chromium-containing oxidant is used to allylically oxidize the allylic compound. Experimentation has shown the specific combination of N-hydroxy dicarboxylic acid imide and chromium-containing oxidant generally provides a superior yield and/or superior quality of allylically oxidized product under mild reaction conditions.
N-hydroxy Dicarboxylic Acid Imide
The N-hydroxy dicarboxylic acid imide includes those formed from dicarboxylic acids which can form cyclic imides in accordance with the general formula: 
wherein X-Y stands for saturated or unsaturated aliphatic hydrocarbon residue, aromatic hydrocarbon residue or a group derived from one of the groups.
Preferred examples of the imide include N-hydroxy succinimide, N-hydroxy-phthalimide, N-hydroxy imides of naphthalene dicarboxylic acids, and derivatives thereof.
Chromium-containing Oxidants
A number of chromium-containing oxidants are known in the art. Preferred examples of chromium-containing oxidants include sodium dichromate monohydrate (SDC), chromium trioxide (CTO), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and chromium perchlorate hexahydrate (CPC).
Both the N-hydroxy dicarboxylic acid imide and chromium-containing oxidants are available from a number of chemical suppliers as an aqueous solution. Since the reaction mixture may include small amounts of water, the oxidants can generally be used as obtained.
Generally, the concentrations of N-hydroxy dicarboxylic acid imide (Imide) and chromium-containing oxidant (Chromium) set forth in Table One below are effective for allylically oxidizing an allylic compound.
Concentrations of less than about 0.5 mole equivalent of chromium-containing oxidant and less than about 0.5 mole equivalents of N-hydroxy dicarboxylic acid imide significantly slows the reaction, while greater than about 3 mole equivalents of chromium-containing oxidant, and greater than about 1.5 mole equivalents of N-hydroxy dicarboxylic acid imide increases the cost of the process without producing a corresponding increase in any beneficial property or characteristic of the process or resultant product(s).
Organic Solvent(s)
The organic reactants (i.e., allylic compound and N-hydroxy dicarboxylic acid imide) can be conveniently dissolved in suitable organic solvent(s), with selection of the solvent dependent upon the specific allylic compound and N-hydroxy dicarboxylic acid imide used.
The solvent should be selected based primarily upon cost and ease of handling, and as well as its ability to dissolve the organic reactants and facilitate reactive contact between the chromium-containing oxidant(s) and the organic reactants. Conventional organic solvents generally suitable for use in the process include specifically, but not exclusively: aliphatic ketones like acetone, aliphatic alkyl nitrites like acetonitrile, and lower alcohols like t-butanol. Such solvents may be used alone or in combination with small amounts of an organic base(s) like pyridine.
Processing Parameters and Procedures
Reaction Time
While dependent upon a number of variables, including the specific allylic compound being oxidized, the specific cooxidants being used and the concentration of reactants within the reaction mixture, the reaction can typically be conducted in about 20 to about 48 hours.
Reaction Temperature
The reaction is preferably conducted at ambient or near ambient temperatures (i.e., temperatures between about 20xc2x0 to 35xc2x0 C.).
Mixing
The reaction mixture should be continuously and vigorously stirred in order to promote contact between the reactants and thereby speed-up the reaction and enhance the yield and/or quality of the desired allylically oxidized organic compound.
Solvent Dilution Factor
As with any solvent-based reaction, the wt % solids should be retained between an upper solubility limiting percentage and a lower reaction rate limiting percentage. As the upper limiting wt % of solids is reached, the viscosity of the resultant reaction mixture increases to such an extent that the necessary molecular interaction of the reactants are limited (e.g., the reaction mixture cannot be effectively mixed, with a resultant loss in yield and/or increased reaction time). Conversely, as the lower limiting wt % of solids is reached, the reaction time begins to increase dramatically due to the reduced opportunity for the reactants to encounter one another within the reaction time. Such low concentrations of solids also results in increased expense due to the excessive amounts of solvent used per unit of reaction product obtained.
While the preferred wt % of solids in the reaction mixtures of this invention depend upon a number of variables, including the specific solvent(s) used and the specific reactants employed, a solids wt % of between about 5 to 20 wt % has been found to be generally acceptable for producing a high yield of good quality product at a reasonable rate of reaction.
Separation and Purification Techniques
Upon completion of the oxidation reaction, the allylically oxidized organic compound can be separated from the solvent system, as well as any unused reactants and any byproducts, by any of a variety of separation techniques known to those skilled in the art, including: (i) dilution, (ii) filtration, (iii) extraction, (iv) evaporation, (v) distillation, (vi) decantation, (vii) crystallization/recrystallization, and/or (viii) chromatography.
The N-hydroxy dicarboxylic acid imide can be substantially recovered from the reaction mixture (i.e., about 80% recovery) simply by (i) filtering the reaction mixture through a bed of celite or similar material (ii) concentrating the organic layer, and (iii) treating the organic layer with toluene, dichloromethane or ethyl acetate.
Any chromium-containing substance(s) can be conveniently removed from the system by (i) evaporating the reaction solvent under vacuum, (ii) re-dissolving the crude solid in dichloromethane or ethyl acetate, and then (iii) filtering the reaction mixture through a bed of celite or similar material.
The isolated allylically oxidized product can be further purified by various known techniques, such as washing the isolated product with a solvent effective for selectively dissolving any remaining contaminants without dissolving appreciable quantities of the product, such as water and/or suitable organic solvents like dichloromethane, ethyl acetate, etc.